The availability of combination antiretroviral therapy has greatly reduced HIV-associated dementia but neurocognitive impairment can still occur earlier in the disease course (conditions collectively known as HAND), and the extent to which earlier impairment improves, persists, or even worsens when on therapy is poorly understood. Also, while it is known that HIV can be found in the CNS and sampled in the CSF, the role of viral replication in the CNS as being contributing or causal to impairment is unknown. Finally, successful suppression of virus in the blood while on therapy is not always accompanied by suppression in the CNS, with this apparent viral replication being a potential contributing factor to a lack of resolution of impairment while on therapy. In this application five senior investigators propose three inter-related projects to study issues surrounding viral replication in the CNS in the setting of antiviral therapy. We believe these studies will provide essential mechanistic information regarding the basis for neurocognitive impairment and that this information is necessary before effective interventions can be designed. The proposal is based on an observational cohort of subjects initiating therapy with longitudinal sampling of blood and CSF from entry through suppression of virus in the blood. Project 1 will focus on evidence of viral replication in the CNS at the time of entry, and on the tropism of this virus (i.e. is it replicating in activated T cells or in macrophage/microglia cells). Project 2 will examine the level of immune-mediated inflammation, and evidence for neuronal damage at entry and their resolution with the initiation on therapy. Neuropsychiatric evaluations will also be done to determine the correlates of neurocogntive impairment and the predictors of it resolution or persistence on therapy. Project 3 will address the issue of persistent viral replication in the CNS while on successful therapy, including defining the tropism of the persisting virus, the role of therapy choice and drug levels in the CNS, and the potential for genetic polymorphism in proteins involved in pumping drugs from the CNS to impact drug concentrations to such an extent as to allow residual, ongoing viral replication. Collectively, these studies will bring a detailed understanding of viral replication and viral evolution, with the attendant issues of inflammation and neuronal damage,